Since the pMDI was introduced in the mid 1950s, inhalation has become the most widely used route for delivering bronchodilator drugs and steroids to the airways of asthmatic patients. Compared with oral administration of bronchodilators, inhalation offers a rapid onset of action and a low instance of systemic side effects. More recently, inhalation from a pressurized inhaler has been a route selected for the administration of other drugs.
The pMDI is dependent upon the propulsive force of a propellant system used in its manufacture to dispense the drug formulation from the device in a form that may be inhaled by a patient. The propellant generally comprises a mixture of liquefied hydrofluorocarbons (HFAs) which are selected to provide the desired vapour pressure and stability of the formulation. Propellants HFA 227 (1,1,1,2,3,3,3-heptafluoropropane) and HFA 134a (1,1,1,2-tetrafluoroethane) are the currently the most widely used propellants in aerosol formulations for inhalation administration.
It has been suggested that hydrocarbons, such as n-butane, isobutanol, and propane be considered as CFC replacements in aerosol formulations. However, it has been found that such hydrocarbons have low densities relative to the pharmaceutically active agents included in the formulations. Where suspension formulations are prepared using such propellants, the formulations sediment rapidly and are unacceptable. Furthermore, the solubility of many drugs in these hydrocarbons is poor, which means that it is difficult to prepare formulations that are solutions which contain suitable amounts of drug.
The formulations currently dispensed using pMDIs generally comprise a pharmaceutically active agent, one or more propellants, and optionally excipients and adjuvants such as co-solvents, (conventional) surfactants, flavouring agents and lubricants.
The excipients should be miscible with the propellants in the amounts employed. Suitable excipients include alcohols such as ethyl alcohol, isopropyl alcohol, propylene glycol, hydrocarbons such as propane, butane, isobutane, pentane, isopentane, neopentane, and other propellants much as those commonly referred to as propellants 11, L2, 114, 113, 142b, 152a 124, and dimethyl ether.
Preferred adjuvants are liquids or gases at room temperature and at atmospheric pressure. The combination of one or more of such adjuvants with a propellant such as HFA 134a or HFA 227 provides a propellant system which has comparable properties to those of propellant systems based on CFCs of the past decades, allowing use of known surfactants and additives in the pharmaceutical formulations. This is particularly advantageous since the safety and use of such compounds in metered dose inhalers for drug delivery to the human lung is well established. Additives that are well know include ethanol, water, glycerol and polyethylene glycol.
The pharmaceutically active agents present in formulations used in pMDIs and similar propellant-driven devices are either dissolved or suspended in a liquefied propellant gas. Most pharmaceutically active agents are not sufficiently soluble in pure propellants, either HFAs or CFCs, for simple two component formulations of active agent and propellant to be practical. Although, through the incorporation of a co-solvent such as ethanol, many active agents can be dissolved in the resulting formulation, formulations in which the active agent, in a micronised or particulate form, is suspended in the propellant are generally preferred and more common. There are several reasons for this. It is important to control the size of the particles or droplets in the aerosol spray produced by a pMDI, or like device. For example, if the particles or droplets are to penetrate deep into the lungs, they should have a mass median aerodynamic diameter (MMAD) of less than 10 μm. Conversely, if the spray is for buccal or nasal delivery, the particles or droplets must have an MMAD of significantly greater than 10 μm, in order to prevent them from entering the lungs. Controlling the size of the particles in an aerosol spray produced from a purely liquid formulation is more difficult than it is with a formulation comprising a suspended solid particulate pharmaceutically active agent. In the former case, many environmentally influenced factors, such as solvent evaporation rates, will have an effect on particle size, whereas the size of the particles produced by a suspension formulation is determined largely by the size of the active agent particles employed in its preparation, and this is a parameter that can be effectively controlled.
A second, but important, reason for suspension formulations being preferred is that many pharmaceutically active agents are chemically more stable as solids than they are when in solution. For example, most pharmaceutically active compounds are much more susceptible to degradation by acid or alkali when in solution than they are when solid. It is also simply impossible to render many pharmaceutically active agents sufficiently soluble in a pharmaceutically acceptable propellant system, for a solution formulation to be a realistic option for them.
A further, reason for suspension formulations being preferred to solutions is that solution formulations may be restricted by the drug loading capacity of the solvent. Drug loading levels will vary depending on the solvent and solute used, however, suspension systems are not limited in this way and routinely allow higher drug loads to be incorporated into the formulations.
Dissolving an active agent to form a solution negates the need to micronise the drug to obtain a suitable particle size. However, not all active agents are stable when in solution or in direct contact with the excipients and propellant.
Previous disclosure, for example by 3M, has demonstrated that the solubility of many drugs may be enhanced in the presence of ethanol. However, high levels of ethanol may impart a negative effect on a suspension system by dissolving the drug.
Dispersing agents, such as surfactants, are commonly employed in suspension aerosol formulations in order to ensure that the particles of pharmaceutically active agent can be dispersed within the propellant system without an undue degree of agitation and remain so dispersed for a sufficiently long period of time for the effective operation of the pMDI to be ensured. Surfactants can also provide useful lubrication to the metering valve's mechanism. However, one of the problems which has arisen in the development of HFA-based suspension formulations for use in pMDI and like devices, is that many of the surfactants commonly employed as dispersing agents in CFC-based formulations are substantially insoluble in HFA 134a and HFA 227 and, thus, are substantially ineffective in simple formulations based on these latter two propellants, or other HFA propellants.
One solution to this problem, which was proposed in EP 0 372 777, is to incorporate a co-solvent, such as ethanol, having a greater polarity than the HFA propellant in the formulation, in order to dissolve the surfactant or other dispersing agent. Whilst the presence of such a co-solvent allows most dispersing agents to be dissolved in HFA based formulations, it will also cause certain pharmaceutically active agents to dissolve, at least partially, in the co-solvent/propellant system. This phenomenon is especially disadvantageous in formulations for delivery into the lungs because, over time, it causes the particles of active agent in the formulation to grow, possibly to a size in excess of that generally considered to be acceptable for inhalation, i.e., to have a MMAD of greater than 10 μm. Further disadvantages associated with the use of ethanol as a co-solvent include its potential toxicity, its capacity to increase a formulation's propensity to absorb water and the fact that many patients dislike the taste that its presence can impart to a formulation.
Another method for incorporating a surfactant or dispersing agent which has been previously proposed is to coat the particles of pharmaceutically active agent with the surfactant or dispersing agent before they are mixed with the propellant and to suspend the coated particles in the HFA propellant without using any co-solvent.
One process which has been proposed in order to achieve such coating involves the steps of dissolving the surfactant in a solvent in which the pharmaceutically active agent is substantially insoluble, mixing a quantity of the pharmaceutically active agent, in micronised form, into the surfactant solution and isolating particles of surfactant coated active agent either by filtration and drying, or by removal of the solvent by evaporation. Although the literature suggests (see WO 92/08447 and WO 91/04011) that formulations prepared in this manner are effective, in the sense that they allow stable dispersions of powdered active agent to be formed in the HFA propellant, it has so far not proven possible, in practice, to manufacture useful formulations in this way. For example, it is difficult to achieve a uniform coating using techniques of this nature because the manner in which the dispersing agent precipitates from the evaporating solvent can be unpredictable.
WO 2006/059152 proposes coating the particles of pharmaceutically active agent with a dispersing agent by fusing solid, particulate dispersing agent to the surfaces of the active particles by mechanical means, such as a milling step. The resulting composite or hybrid particles are readily dispersible within HFA propellant systems.
A further technique which has been proposed is to suspend a powdered mixture consisting of particles of a calcium, magnesium or zinc salt of palmitic or stearic acid and particles of pharmaceutically active agent in the propellant.
A further problem that is often associated with known formulations for delivery using devices such as pMDIs is their stability and consequently their shelf life. This especially applies to ethanol-free suspension formulations. These formulations and the pMDI products have a reduced shelf life due to moisture ingress. Generally, when the formulations are prepared they are free of moisture. However, once opened from their foil packaging, the shelf life of the pMDI formulation is dramatically reduced due to the ingress of moisture. The ingress of moisture can change the suspension characteristics, often leading to increased flocculation rate which leads to poor product performance and poor drug delivery.
It is an aim of the present invention to provide improved suspension formulations comprising a pharmaceutically active agent for delivery using a spray or aerosol device, such as a pressurised metered dose inhaler (pMDI).
In particular, it is desirable for the active agent within the suspension formulations to be stable, so that the physical and chemical state of the active agent is retained when the formulation is made and over time as it is stored and used. More specifically, it is an aim of the present invention to provide suspension formulations that allow the delivery of an active agent in amorphous form (and therefore exhibiting preferable dissolution characteristics).
It is also an aim of the present invention to provide a suspension formulation in which the suspension itself is physically stable, in that it exhibits a reduced tendency to flocculate and/or for the suspended particles to sediment. It is also an aim of the present invention to provide suspension formulations with a long shelf-life and, in particular, formulations that are not sensitive to moisture ingress.